This is a competing renewal submission for Project 1 of the NIDA Program Project "FMRI of Cocaine Action". The objective of this project is to investigate the brain reward circuitry mediating cocaine response the regional activation of brain reward circuitry in response to acute cocaine infusion are consistent across subjects. This work further suggests a dissociation of brain region s active during euphoria and during craving. Specifically, we find that the nucleus accumbens, basal forebrain, amygdala and ventral tegmentum consistently show distinct changes in fMRI signal that correlate with euphoria and craving in response to cocaine. The function of each of these regions with regard to brain reward is complex; presumably, these regions interact to produce discrete aspects of cocaine addiction such as euphoria, craving, expectancy, and cognitive choice for self-administration. In this Project we propose to investigate the role of each of these brain regions during cocaine-induced euphoria and craving. Specific Aim #1 is designed to evaluate the stability of the fMRI response to cocaine infusions in cocaine-dependent subjects. Experiments will focus on producing euphoria and craving, and test the hypothesis that reward circuitry will demonstrate consistent activation over time, a reproducible dose response, and rapid tolerance coordinated with subjective ratings during serial closely-spaced cocaine infusions. Specific Aim #2 will investigate the function of explicit cognitive and reward prediction processes on the fMRI response to cocaine infusion. Specifically, we will study the impact of reward expectancy and of decision-making for self- administration on fMRI response. In Specific Aim #3 we will evaluate the specificity of reward circuitry by comparing the fMRI pattern of brain activation and euphoric response in the same subjects following infusion of cocaine and the short-acting, mu opioid agonist remifentanil. Our core hypothesis for the proposed experiments is that distinct temporal patterns of events in brain reward circuitry, and other regions associated with reward, mediate cocaine-specific behavioral responses. These experiments will allow us to determine the roles of specific sub-cortical structures that mediate brain reward and underlie cocaine-induced euphoria and craving, thus significantly improving our understanding of the mechanisms maintaining cocaine dependence.